This invention relates to a process for methylating a hindered nitrogen atom in the diazacycloalkane ring of a piperazine or piperazin-2-one which is substituted at both the 3- and 5- positions of the diaza ring. Such compounds are referred to as polysubstituted piperazine or piperazinone ("PSP" for brevity) compounds. The N.sup.4 atom is hindered in all such PSPs. This N.sup.4 atom is termed "the hindered N atom" because it is flanked by disubstituted 3- and 5-carbon atoms, either or both of which may have a spiro substituent. Compounds containing one or more PSP substituents are referred to as "PSP-substituted" compounds. An example of such compounds are triazine compounds having PSP substituents. The process of this invention is specifically related to the methylation of PSP-substituted triazine compounds. Methylated PSP-substituted triazine compounds are excellent stabilizers for polyoxymethylene resins, particularly polyacetals.
Hindered amines having a methylated hindered N atom, are highly desirable stabilizers for synthetic resinous materials, and command a premium price in the marketplace, whether the amine is a piperidine, piperazine or a piperazin-2-one derivative. Several methylated PSP stabilizers have been disclosed in Japanese patent application 63-86711 published Apr. 18, 1988. These stabilizers are said to improve the color of polyacetals though the PSPs are not connected to a triazine ring. There is no teaching of how such methylated compounds were prepared, but it is known that the high cost of producing the stabilizers confines their syntheses to the laboratory. Our process is directed to providing an economical solution to a difficult manufacturing problem.
The general process is described under the heading "Methylation of Amines with Formaldehyde" in Organic Reactions, Vol V by M. L. Moore, pg 307 et seq., as follows: One molecular proportion (or slight excess) of formaldehyde and two to four molecular proportions of formic acid are used for each methyl group introduced, indicating that it is mainly the formic acid that supplies the hydrogen involved in the reduction. The reaction is carried out on a steam bath. This variant of the Leuckart reaction is commonly known as the Eschweiler-Clarke ("E-C" for brevity) procedure.
The typical E-C reaction, carried out with a primary or secondary amine, results in the methylated amine only when heated for several hours after the evolution of gas has ceased due to reaction with an excess of formaldehyde and an excess of formic acid in an aqueous medium. The formic acid functions as both a co-reactant and a solvent. The function of formic acid as a solvent is particularly important when the amine to be methylated is poorly soluble in water.
Unhindered amines such as benzylamine and piperazine are expected to react to give almost theoretical yields of the corresponding tertiary amines. But in practice, they do not. It is therefore not surprising that hindered amines, which are are not expected to be essentially completely methylated by virtue of being hindered, should not be. The overall yield from the PSP-substituted triazine starting material is further reduced by the difficulty of recovering the desired product from the reaction mass ("work-up"). The result is substantially lower than theoretical yields from a high-priced starting material, and the low yields make the process uneconomic.
In a text-book procedure for a typical E-C reaction (see Moore, supra pg 323), benzylamine (1 mole) is added with cooling, to 5 moles of 90% formic acid. Then 2.2 moles of 35% formaldehyde solution is added, and the mixture is heated on a steam bath under reflux for 2 to 4 hours after evolution of gas has ceased (8 to 12 hr in all). Slightly more than 1 mole of concentrated hydrochloric acid is then added and the formic acid and any excess formaldehyde are evaporated on a steam bath. The colorless residue is dissolved in water and made alkaline by the addition of 25% aqueous sodium hydroxide, and distilled over sodium. The product, N,N-dimethylbenzylamine is recovered in about 80% yield. The unacceptability of such an yield in a commercial process is exacerbated by the very long time required for the reaction, time being an essential consideration in the economics of a process.
Despite the evident advantages of using water both as a solvent and as reaction medium, carrying out this reaction commercially is burdened with the costs of recovering the large excess of formaldehyde or formic acid, or both. For example, Czech appln. No. 82/5562 filed Jul. 21, 1982 discloses treating the methylated product with HCl, then distilling under vacuum to remove volatiles. The yield was 66-70% which is commercially unacceptable because of the high cost of PSP-substituted amine to be methylated. Such a distillation process still leaves the problem of separating the large excess of formic acid from the formaldehyde.
Separating formaldehyde and formic acid as aqueous solutions of chosen concentration (which may later be diluted) by distillation, is not practical because of the too-close boiling points. For example, USSR appln No. 80/22299, filed Oct. 10, 1980 discloses distillation in a column the pressure at the top and bottom of which was 20 mm and 2 atm respectively. Even if one was prepared to bear the cost of neutralizing formic acid, disposing of sodium formate solution is expensive; and one still has to deal with recovering, or disposing of the formaldehyde, for example by biological detoxification.
The foregoing general E-C procedure was followed with particular regard to a light stabilizer containing plural PSP substituents. UK Patent application GB 2194237A published Mar. 2, 1988, example 1 discloses preparation of a tetramine containing plural triazine rings, each substituted with two pentamethylated piperidyl substituents. The amine to be methylated is N.sup.1,N.sup.2, N.sup.3,N.sup.4 -tetrakis-[2,4-bis[N-(2,2,6,6-tetramethyl-4-piperidyl)-n-butylamino]-1,3,5 -triazin-6-yl]-4,7-diazadecane-1,10-diamine, and it has 8 tetramethyl-4-piperidyl substituents. To a solution of 0.02 moles of this amine in 100 ml of water is added 0.4 moles of formic acid and 0.4 moles of a 40% aqueous formaldehyde solution (each a 2-fold molar excess with terminal --NH groups). The solution is heated under reflux for 8 hr; after cooling to room temperature, an additional amount of 0.2 moles (stoichiometric) of 40% formaldehyde is added and the solution refluxed for an additional 5 hr.
In the foregoing E-C procedure, as in most of the Leuckart reactions, the reactions are carried out in the absence of any solvent other than the reagents themselves. However, nitrobenzene has been used as a solvent with a few ketones that were insoluble in the hot reaction mixture, and it has been used to increase the reflux temperature of reaction mixtures containing low boiling ketones (Moore, supra, bridging pgs 317-318).
In E-C reactions where the amine reactant is soluble in formic acid, and it is desired to keep the water to a minimum, essentially pure paraformaldehyde and the highest concentration of commercially available formic acid (above 95% HCOOH) is used, with no additional solvent added to the reaction mass. But such a reaction also requires a large excess of formic acid. The excess formic acid is difficult to recover and reuse. Addition of a non-aqueous solvent does not make recovery of the product and recovery of the formic acid easier. Hence, a commercial E-C process uses readily available aqueous solutions of formaldehyde and formic acid, and no additional solvent if the presence of water does not slow down the reaction too much. If economics require that the temperature at which the reaction proceeds be substantially higher than 100.degree. C., a reactor must be maintained under substantially elevated pressure, which adds to the difficulty and cost of producing product.
Thus, given the practical necessity of using commercially available aqueous formic acid and formaldehyde, it would not seem that adding an additional solvent to the reaction system would serve any useful purpose. Particularly adding a water-immiscible solvent for the reactants and the methylated product would be at cross-purposes with the accepted function of water in the reaction since its function would be usurped by the solvent. Under such circumstances the duration of the reaction would be expected to be increased, not shortened. It could not have been foreseen that adding an alkylbenzene solvent would provide any significant benefit, either under "essentially dry" or essentially non-aqueous conditions, or under aqueous or "wet" conditions.
By "essentially dry" conditions we refer to a reaction mass which has less than 3% by weight (wt) water present after the reaction is complete and the reaction mass is essentially a single organic phase. The use of paraformaldehyde, or concentrated formaldehyde, and formic acid (85% HCOOH or higher), dictates that a little water be present, the amount of water increasing if the PSP or PSP-substituted reactant is moist (water not removed). By "wet" conditions we refer to a reaction mass in which there is at least 3% by wt water, but no more than about 30% by wt water, so that both aqueous and organic liquid phases are visually discernible. In either case, when the reaction is carried out at above about 60.degree. C. CO.sub.2 formed during the reaction is driven off. A higher temperature shortens the time for the reaction, producing the methylated tertiary amine, substantially quantitatively, typically in less than 8 hr.
Neither could it have been foreseen that, when the reaction is carried out in the presence of a sufficient amount of an alkylbenzene solvent to maintain the reactants in solution and provide less than 30% by weight of water in the reaction mass, the methylated product remains essentially completely in the alkylbenzene. This allows the reaction mass to be washed with water. By "solvent phase" we refer to the solution of organic material in the alkylbenzene solvent. This ability to wash out essentially all impurities from the solvent phase, including unreacted formaldehyde, formic acid and salt formed upon neutralization, enhances the efficiency of, and vastly simplifies the recovery procedure for the methylated product.
It will be evident from the foregoing, that the steps under which adequate conversion is obtained in a reasonable amount of time, and the steps of a work-up using a favorable partition coefficient under process conditions provided in the recovery system, must together provide an actual yield of essentially pure product high enough to make the process commercially successful.
Some of the foregoing considerations are indicated in a process for the methylation of triazine compounds containing 2,2,6,6-tetramethylpiperidine groups, disclosed by Piccinelli et al in European patent application 0319480 published June 6, 1989. The peculiar characteristics of triazine compounds containing such piperidyl groups requires that, if paraformaldehyde is substituted for 30-50% (weight/volume) aqueous formaldehyde, then the paraformaldehyde is suspended in water in a quantity necessary to obtain a CH.sub.2 O concentration equal to 30-50%. Moreover, the reaction is carried out in the presence of aqueous alkali which almost completely eliminates CO.sub.2 produced in the reaction.
Our process relates specifically to a modification of the well-known E-C procedure, which modification makes it possible to prepare PSPs and PSP-substituted compounds containing a methylated hindered N atom, on a commercial scale, economically. Our process is carried out in the presence of an inert organic liquid medium which is a solvent for the reactants and the desired methylated product, the solvent being chosen for its favorable partition coefficient for the methylated product in an aqueous system. The solvent is preferably an aromatic liquid such as an alkyl benzene chosen from ethylbenzene, trimethylbenzene, xylene, and most preferably toluene. The compound to be methylated is dispersed in the solvent and the reaction is carried out with a specified slight excess of paraformaldehyde and formic acid. Unlike an E-C methylation of piperidyl-substituted triazines, aqueous alkali is added only after the methylation reaction is complete, since the boost due to the reducing action of the alkali metal salt is not only unnecessary in our E-C reaction, it serves only to pre-neutralize formic acid. By "inert" we refer to a solvent which is unreactive with the compounds in the reaction mass under the conditions of the reaction.